Peter Attia - John Kastelein

1) John Kastelein discusses the different types of diseases, including familial hypercholesterolemia (FH), and how they can be preventable with proper education and treatment. Additionally, John Casteline notes that FH is a true autosomal dominant disease, meaning that if one's parents have the condition, they are almost certain to get the phenotype.

2) John Kastelein discusses the objective metric for diagnosing FH, which is history first and very often. They also explain that in families with FH, there is a family history of premature coronary disease, that this is one of the first things that speaks for the family, and that then second, these people have elevated LDL cholesterol without any other abnormality. Lastly, John Casteline discusses the use of children as a diagnostic linchpin for FH. They state that if a child has high cholesterol with the exception of primary hypothyroidism, there is almost no other cause for elevated LDL cholesterol in a child.

3) John discusses the different mutations that can lead to elevated LDL cholesterol levels. They also describe how LDL receptor mutations can lead to a loss of function of the LDL receptor and increased levels of cytosterol and composterol.

4) John discusses the idea that a log-fold higher level of cholesterol in the blood is associated with an increased risk of heart disease and other chronic diseases. The three genetic mutations that are most commonly associated with high cholesterol levels are ABC G5 G8, which is a mutation in the ABC transporter gene, and a loss of function mutation in the arcus cornealis gene. These mutations may lead to increased accumulation of cholesterol in the body's tissues, which can be seen physically as xanthomas or fat deposits in different parts of the body. Finally, he goes on to discuss the idea that if a person is heterozygous for a loss of function mutation in the ABC transporter gene, they also have increased Campestral levels and a higher chance of having an increase in plant sterols in their blood.

5) John explains that there is a cholesterol overlap between people with heterogeneous FH and people with monogenic FH, and that the two forms of heterozygous FH are much more common. He also discusses the importance of family members history and archives, and how this information can help to determine if a person meets criteria for FH.

6) John discusses the Dutch lipid clinic's criteria for diagnosing FH, and how these criteria may differ from other criteria. They also discuss the impact of FH on the lifespan of a person.

7) John discusses the various diseases that are treatable with treatments that increase HDL levels, such as mutations in cholesterol genes. The vast majority of these diseases are women, and they are usually discovered when a child is referred for total cholesterol levels, which are then measured by their father and mother. John then discusses the various lifestyle factors that may lead to resistance against elevated LDL cholesterol. For example, smokers are almost never resistant to elevated LDL cholesterol, and diabetes is almost never resistance to elevated LDL cholesterol. However, John also discusses the study that found one family with a mutation in one of their cholesterol genes had very high HDL levels, but they had premature coronary disease.

8) John talks about how different treatments for FH (heterozygous for FH) are different based on the age at which the person was treated and whether they were in primary or secondary prevention. They discuss saturated fat restrictions and the role that LDL cholesterol levels play inFH.

9) John discusses the various benefits and drawbacks of statin use in children and adults. He mentions that statins can impair cholesterol synthesis and maybe in a developing child that could be problematic, but a pcsk9 inhibitor has no bearing on cholesterol synthesis. John also agrees that statins are useless in the embryonic stage and that during the most important period of development, when their brain is developing, pcsk9 has a role in brain development. Finally, John argues that statins are not effective in the presence of Resististat and atorvastatin.

10) John explains that there are many different causes of heart disease, including genetic diseases, and that it is very difficult to find people with high LDL cholesterol who do not have coronary artery disease.

11) John discusses the role of c-tep inhibitors in modulating risk for heart disease and cancer. He talks about the discovery of a protein that binds to cholesterol esters, which leads to lowered cholesterol levels and improved health. c-tep inhibitors are also used to treat age-related cognitive diseases, such as Alzheimer's disease.

12) John talks about the history of cholesterol and how it has been used as an excuse for a lot of diseases. He also discusses the idea that LDL cholesterol is only important in the presence of high HDL cholesterol. They also talk about the concept of the Thrifty Gene hypothesis which explains why people with type 2 diabetes are more likely to have high HDL cholesterol.

13) John discusses the potential benefits and drawbacks of a new drug called ta-8995. They also argue that FH is not such a severe disease as it is currently and that there may be more FH because of increased levels of cholesterol.

14) John discusses the results of a study that found that those who have a loss of function variant in CTP are much better protected against septicemia. They also discuss the results of a study that found that those who have a loss of function variant in CTP are also more likely to have a high HDL cholesterol level.

15) John is discussing the progress of a study looking at the impact of CTP inhibitors on health. They mention that the study is currently in phase three, and that all the trials have been completed.

16) John discusses the different trials that are currently being conducted in order to find a new, better lipid-lowering drug. They state that the drug is cheap to make and is very effective. Additionally, they mention that the drug may have some benefits for the brain and heart.

17) John discusses the role of LDL cholesterol in heart disease, the benefits of pcsk9 inhibitors, and the potential risks of the drug Prevail.

18) John discusses the finding that certain medications, such as statins, reduce heart disease and cognitive decline. They also mention that there is a large psychological component to this disease, and that statins may not be the best choice for everyone.

19) John is discussing the role of Apple A1 in Alzheimer's disease, familial hypercholesterolemia, and blood pressure. They mention that there is no simple explanation for why blood pressure increases when CDP is inhibited, and that this is a problem because Apple A1 is an insufficient molecule to get cholesterol out of cells in the brain that have too much or bring cholesterol to cells in the brain that have too little. They also mention that if blood pressure levels increase too much in an apple E4 carrier, they will push the molecule into the brain and it will eventually convert to 24 hydroxycholesterol.

20) John discusses the complex nature of apoe4, the three isoforms of apoe4, and how this affects cholesterol metabolism. They also mention a study that has already shown that apoe4 carriers are almost completely protected from Alzheimer's disease.

21) John provides a brief overview of the role of APO e in cardiovascular disease. They discuss the idea that apoe gets a lot of attention because of its role in the brain, but they are less clear on the relationship between apoe and atherosclerosis and apoe in terms of risk for vanished. They also discuss the role of Apple E4 in cardiovascular disease and how it might lead to increased LDL clearance.